"Trapped fat: Obesity pathogenesis as an intrinsic disorder in metabolic fuel partitioning"

This new paper emphasizes fuel partitioning and de-emphasizes energy intake as a cause of obesity, and I think that's backward.
doi.org/10.1111/obr.13… To illustrate this, I'm going to focus on one section of the paper that's in my wheelhouse:

The argument that lesions of the ventromedial hypothalamus (VMH) in animals cause obesity mainly due to fuel partitioning effects rather than increased energy intake.

This recent study by @KevinH_PhD is awesome.

It investigates the impact of different weight loss methods on the "lipostat"-- the body fat regulatory system in the brain that opposes weight loss efforts.

My plain language summary.
doi.org/10.1002/oby.24… We all know that weight loss, and especially weight loss maintenance, is challenging.

Most people who attempt to lose weight using diet and exercise lose some weight and then regain most of it over time.

Folks, nutrition research has an insanely big problem, detailed in a new piece by @cremieuxrecueil.

If you make a histogram of p-values from a body of research, if there are no shenanigans the curve should fall between the two below.
cremieux.substack.com/p/ranking-fiel… This is what the curve looks like for nutrition research.

In lieu of a string of curse words, I'm going to go with YIKES.

I want to float an idea for discussion and feedback.

What if we greatly lowered the bar for prescribing fat loss drugs?

E.g., a person who just wants to lose 20 lbs has a quick doctor's appointment and gets a scipt for a low dose of GLP-1 RA. Let me emphasize that I'm not arguing for this right now. I'm just getting the idea out there for discussion.

@patrickc There's another RCT of psychological treatment for chronic back pain that is more rigorous and found larger effect sizes
jamanetwork.com/journals/jamap… @patrickc I don't think anyone can claim the concept is woo at this point

Leptin is the primary hormone that has been implicated in the regulation of body fatness in mammals.

This is a quick thread covering some of the evidence that its primary site of action is the brain. Jeff Friedman's group was the first to provide evidence in this 2001 paper. They showed that partially deleting the leptin receptor in neurons specifically caused mice to develop obesity.
doi.org/10.1172%2FJCI1…

A recent study examines what happens when the new weight loss drug semaglutide (Wegovy) is withdrawn after 68 weeks of treatment. Some interesting things to chew on in this paper.

h/t @kamleshkhunti
doi.org/10.1111/dom.14… Let's take a look at the graph of weight change over time.

People with obesity treated with semaglutide lost 17% of body weight over 68 wk.

They regained most of it over 52 wk after drug withdrawal.

Nudging @bigfatsurprise to please issue a correction for this tweet. The US diet was ~45% carbohydrate in 1977.

The tweet was liked more than 700 times and I'm sure these people would appreciate knowing.

https://twitter.com/bigfatsurprise/status/1522742757470740482

If we follow the citation in the tweet, it leads to the 1977 Dietary Goals for the US document, which contains the following table (h/t @Natural_Fallacy)
naldc.nal.usda.gov/catalog/1759572

This is huge. Eli Lilly is reporting *average* weight loss of 20.9% of body weight for the highest dose of tirzepatide in people with obesity over 72 wk in the phase 3 SURMOUNT-1 trial.
investor.lilly.com/news-releases/… This is an intention-to-treat estimate, meaning the average *includes* people who stopped taking the drug (15% dropout at highest dose).

This weight loss comes very close to gold-standard bariatric surgery.

Glad to see this paper out from @KevinH_PhD and colleagues.

This sets the record straight on some issues related to obesity science that have been under recent debate.

It's a response to @davidludwigmd recent review paper on the carb-insulin model of obesity.

https://twitter.com/KevinH_PhD/status/1489622951712354308

This is the paper it's responding to.

There are a few things I found hard to understand in this paper.

One is the misrepresentation of alternative models of obesity, pitting CIM against an obsolete model that virtually no one believes.
doi.org/10.1093/ajcn/n…

It seems that some people would like to understand this better. So here we go.

https://twitter.com/whsource/status/1488171720817078275

For most wild animals, obtaining energy (calories) is the most important goal of foraging. How do we know that?

A large body of research suggests that the foraging behavior of many species can be predicted by the energy return rate of foraging options.
en.wikipedia.org/wiki/Optimal_f…

"Toward a Wiring Diagram Understanding of Appetite Control"

Awesome paper that I don't recall having seen

In researching for my book, my goal was a wiring-diagram-level understanding of how the brain turns internal/external cues into eating behavior
doi.org/10.1016/j.neur… We don't have a full wiring-diagram-level understanding of how this works yet, but I'm continually amazed at how much progress has been made recently.

Obesity is caused by a gene-by-environment interaction.

In other words, genetics loads the gun, the fattening environment pulls the trigger.

A new paper aims to identify what in the diet "pulls the trigger" in genetically susceptible people.
doi.org/10.1093/jn/nxa… They used a composite score of genetic susceptibility to obesity, and a diet questionnaire, to determine if diet variables "explain" how genes make us fat.

This method has limitations I'll discuss shortly.

Back in my early blogging days, one of my soapbox issues was that dietary saturated fat is probably harmless.

My views on that have evolved over the years and it's time for me to share the update. At the time I wrote about saturated fat, it was the halcyon days of the ancestral health movement.

There was a lot of good in the movement but it had more than a little anti-establishment animus, and that bled into my writing.

A new randomized controlled trial provides striking support for a psychological approach to chronic pain treatment.
jamanetwork.com/journals/jamap… This is a well-powered, preregistered trial, with a single primary outcome in both the registry and the published paper.

That's what I like to see!
clinicaltrials.gov/ct2/show/NCT03…

David Ludwig was pleased with my recent comments on his new review paper. I’m glad they came across as respectful.

However, I still think the CIM is probably incorrect, and its advocates aren’t acknowledging the strength & breadth of contrary evidence.

https://twitter.com/davidludwigmd/status/1438221501702950912

On the ConscienHealth site, Ludwig wrote:

“After repeated (>12) dismissals of the CIM with weak & confounded evidence, what I would like to see is rigorous debate of the science.”

This characterization, which refers in part to my writing, is inaccurate.
conscienhealth.org/2021/09/obesit…

Some of you may recall the meta-analysis of controlled feeding trials by @davidludwigmd arguing that low-carb diets lead to higher energy expenditure vs. high-carb diets, after an adaptation period.

@KevinH_PhD and I re-analyzed the data (free access).
doi.org/10.1093/jn/nxa… Long story short, I'm fairly convinced that there is actually an effect consistent with what @davidludwigmd suggests, but we think the effect size is smaller than reported.

Our analysis suggests that it amounts to less than the kcal value of an apple per day.

Hold on to your hats, folks. Here’s my summary of the recent paper by @eatlikeanimals.

700 male C57BL/6J mice, 33 different diets, 12-19 weeks to study interactions between protein quantity & carbohydrate type in determining fatness & metabolic health.
nature.com/articles/s4225… C57BL/6J mice are often used for this type of study because they are susceptible to human-like obesity and metabolic dysfunction.

This study is a beast so I’m only going to cover a fraction of the findings, primarily focusing on body fatness outcomes.

"Are people with metabolically healthy obesity really healthy?"

11.2 year follow-up of 381,363 people.

Overall, people with "metabolically healthy obesity" were intermediate in risk between lean/healthy and obesity/unhealthy.

h/t @DanielJDrucker
link.springer.com/article/10.100… There's a big caveat though. "Metabolically healthy obesity" was defined as meeting 4 out of 6 cardiometabolic health metrics.

Wanted to offer my interpretation of this finding.

The strongest genetic signature associated with fasting insulin level in this study was with adipose tissue, and particularly adipose tissue insulin resistance.

The adrenal glands and muscle were also implicated.

https://twitter.com/whsource/status/1399737359478841344

This points to insulin resistance as the main driver of common hyperinsulinemia, especially IR in adipose and muscle tissue. Helps resolve the "chicken and egg" question.

The adrenal glands may contribute via the stress hormone cortisol, which reduces insulin sensitivity.

New genome-wide association study points to tissues and mechanisms responsible for common variation in fasting insulin level.

Adipose tissue, adrenal glands, muscle, and "blood cells" implicated. Surprisingly, not the pancreas or brain.
doi.org/10.1038/s41588… The most impactful variant they identified is associated with expression of the insulin receptor in adipose tissue.

Suggests that lower insulin sensitivity in adipose tissue leads to higher fasting insulin level. Makes sense.